Synthesis of a salbutamol dimer

Article abstract of DOI:10.1016/S0040-4039(01)02354-1

First synthesis of the diastereomeric mixture of Salbutamol dimer (2) is described. The synthesis provides access to multi-gram quantities of 2 for reference supplies and further analytical and toxicology investigations. It also confirmed the proposed str

Full text of DOI:10.1016/S0040-4039(01)02354-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1135–1137
Synthesis of a salbutamol dimer†
Nizar Haddad,* Yibo Xu, James A. Baron and Nathan K. Yee
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals Inc, 900 Ridgebury Rd./PO Box 368, Ridgefield,
CT 06877-0368, USA
Received 7 November 2001; accepted 12 December 2001
Abstract—First synthesis of the diastereomeric mixture of Salbutamol dimer (2) is described. The synthesis provides access to
multi-gram quantities of 2 for reference supplies and further analytical and toxicology investigations. It also confirmed the
proposed structure by comparison to authentic sample. © 2002 Elsevier Science Ltd. All rights reserved.
Salbutamol (1), a potent b2-adrenoceptor agonist, is
effective as a bronchial smooth muscle relaxant. Cur-
rently it is considered, in its racemic form, as one of the
most prescribed bronchodilators for the treatment of
bronchial asthma.1 Since its development in the late
1960’s, the continuous effort for the separation and
structure determination of related impurities,2,3
obtained during the synthesis or upon prolonged stor-
age of the drug, is still of interest. Special attention was
focused on the mixture of its dimeric ‘side-by-side’
impurities2 2, usually detected in ca. 0.05–0.1% in
salbutamol batches. To the best of our knowledge,
there are neither reported synthesis nor unambiguous
structure determination of these proposed dimeric
structures (Fig. 1).
Initial efforts focused on the direct preparation of 2 via
dimerization of Salbutamol under a variety of acidic
conditions (HCl, pTsOH, CSA with different solvents
and temperatures).4,5 Unfortunately, no traces of the
desired product could be detected by HPLC upon
comparison to authentic sample. The following synthe-
sis of 2 was then developed.
Two approaches were examined for the preparation of
the key starting material 6: (a) Coupling of bromophe-
nol with the commercially available triol 3 under acidic
conditions. Unfortunately, double condensation
product 4 and triol 3 were the major compounds
detected in these attempts (Scheme 1); (b) Baekelite
condensation of p-bromophenol with formaldehyde
provided 5 in 94% yield.5a Treatment of 5 with
paraformaldehyde and NaOH provided 6 in 38% iso-
lated yield.5b Acetate protection of the triol was
expected to hold and to increase the solubility of the
intermediates throughout the synthesis. Treatment of 6
with acetic anhydride provided 7 in 94% yield.
OH
OH
OH
OH
OH
H2SO4
OH
OH
OH
NH
NH
NH
2
OH
OH
OH
OH
1
2
Salbutamol
(Albuterol Sulfate)
OH
HO
"side-by-side" dimer
Br
Figure 1.
Br
Br
Br
4
In order to confirm the structures 2 and also provide an
easy access to these compounds for reference supplies,
further analytical and toxicology investigations, a syn-
thesis of the diastereomeric mixture was desirable.
Herein, we describe the first synthesis of 2.
3
Scheme 1.
Stille coupling3,6 of 7 with tri-n-butylvinyltin afforded 8
in 50% isolated yield. Direct epoxidation of 8 with
MCPBA was first examined and resulted in low yield of
the desired bis-epoxide 10. Alternatively, 10 was pre-
pared upon treatment of 8 with NBS in wet DMSO7 to
* Corresponding author.
†
Presented in part at the 221st ACS National Meeting, San Diego,
April 2001, ORGN 325.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02354-1

1136
N. Haddad et al. / Tetrahedron Letters 43 (2002) 1135–1137
OH
OH
OH
OH
OH
Br
Ac2O
OH
HCHO, H2SO4
HCHO, NaOH
DMAP (cat.)
Pyridin, 2h
50oC, 72h
38%
-10-0oC, 18h
94%
Br
Br
Br
Br
94%
5
6
OAc
OAc
OAc
OAc
OAc
OAc
OAc
SnBu3
OAc
NaH
NBS
OAc
PdCl2(PPh3)2
PhMe, 95oC
50%
DMSO/H2O
0.5h
DMF/THF
0.5h
57%
Br
Br
OH
OH
7
98%
Br
Br
9
8
OH
OH
OAc
OAc
OAc
OAc
OH
OAc
tBuNH2/
i-PrOH (1:1)
OAc
N2H4/MeOH
reflux, 1h
74%
OH
OH
OH
OH
14
Reflux, 2h
66%
NH
NH
NH
NH
O
O
2
10
Scheme 2.
give 9 in 98% yield, followed by cyclization with NaH
to give 10 in 57% yield (Scheme 2).
diastereomers was obtained. Careful comparison with
authentic sample was carried out by H NMR, MS and
HPLC. Complete match was obtained in all these
experiments, providing for the first time unambiguous
confirmation of the chemical structure of 2.
1
A regioselective addition of tBuNH2 to the epoxide was
expected.3,8 However, it should be noted that treatment
of 11 with tBuNH2 in isopropanol under reflux for 4 h
provided 12 in 70% isolated yield, presumably via inter-
mediate 13 (Scheme 3). Interestingly, treatment of 10
with tBuNH2 in isopropanol (1:1) under reflux for 2 h,
provided 14 in 66% isolated yield with no detectable
amount of 15 by NMR.
Acknowledgements
The authors acknowledge Dr. Karl Grozinger for useful
discussion, Dr. Jan Glinski for authentic sample of 2
and Mr. Scot Campbell for assistance in the NMR.
OAc
OH
tert-BuNH2/i-PrOH (1:1)
OAc
N
H
Reflux, 4h
70%
References
Br
Br
12
11
1. Bakale, R. P. Specialty Chem. Prod. Market Applic. 1995,
15, 249; Caira, M. R.; Hunter, R.; Nassimbeni, L. R.;
Stevens, A. T. Tetrahedron: Asymmetry 1999, 10, 2175.
Review on drug evaluation of Salbutamol, see: Stephen, A.
H.; Clissold, S. P. Drugs 1989, 38, 77.
2. Different ‘side-by-side’ dimeric structures were reported in
Refs. 2a and 2b: (a) Altria, K. D. J. Chromatography 1993,
636, 125; Altria, K. D. J. Chromatography 1993, 634, 323;
(b) Altria, K. D.; Luscombe, D. C. M. J. Pharm. Biomed.
Anal. 1993, 11, 415; Rogan, M. M.; Altria, K. D.;
Goodall, D. M. Electrophoresis 1994, 15, 808.
OAc
OAc
OAc
N
H
OH
OH
15
Br
NH
NH
13
Scheme 3.
Hydrolysis of the acetate groups was examined under a
variety of conditions including K2CO3, NaOH, Al2O3,
KCN, Mg/MeOH and NaBH4, in all cases the product
could not be isolated in sufficient yield. However, reflux
of 14 with hydrazine/MeOH afforded the desired final
product (2) in 74% isolated yield after purification on
C18-preparative column followed by crystallization
from EtOAc.9
3. Yee, N. K.; Nummy, L. J.; Roth, P. R. Bioorg. Med.
Chem. Lett. 1996, 6, 2279.
4. (a) Gutsche, C. D.; No, K. H. J. Org. Chem. 1982, 47,
2708; (b) No, K.; Kim, J. E.; Kim, S. J. Bull. Korean
Chem. Soc. 1996, 17, 869.
5. (a) Hosein, H. G.; Ali Akbar, M. Helv. Chim. Acta; Eng.
1981, 64, 599; (b) No, K.; Kwon, K. M. Synthesis 1996,
1293.
6. McKean, D. R.; Parrinello, G.; Renaldo, A. F.; Stille, J.
The NMR spectra of 2 was recorded in D2O and
almost complete overlap of chemical shifts of the
K. J. Org. Chem. 1987, 52, 422.
7. Tanner, D. D.; Stein, A. R. J. Org. Chem. 1988, 53, 1642.

N. Haddad et al. / Tetrahedron Letters 43 (2002) 1135–1137
1137
8. Hett, R.; Stare, R.; Helquist, P. Tetrahedron Lett. 1994,
Hz), 7.08 (1H, d, J=7.7 Hz), 7.13 (1H, s), 7.26 (1H, s),
7.29 (1H, s); 13C NMR (125.7574 MHz, CDCl3) l: 27.7,
35.5, 50.4, 60.0, 63.2, 72.3 (×2), 120.7, 127.5, 128.7, 129.9,
130.5, 131.5, 131.7, 131.8, 133.2, 133.4, 159.2, 161.7;
HRMS calcd for (M+H)+ C26H41N2O5: 461.3020, found
461.3015.
35, 9375.
1
9. All new compounds were characterized by H, 13C NMR,
and MS spectroscopy. Dimer 2: 1H NMR (500.1325
MHz, D2O) l: 1.34 (18H, s), 3.19 (3H, s), 3.86 (2H, s),
4.62 (2H, s), 4.81 (2H, d, J=6.5 Hz), 6.74 (1H, d, J=8.64